U.S. patent number 6,635,645 [Application Number 09/856,946] was granted by the patent office on 2003-10-21 for 2,5,-diazabicyclo[2.2.1]heptane derivatives, their preparation and therapeutic uses.
This patent grant is currently assigned to Sanofi-Synthelabo. Invention is credited to Luc Even, Frederic Galli, Samir Jegham, Jean Jeunesse, Alistair Lochead, Alain Nedelec.
United States Patent |
6,635,645 |
Lochead , et al. |
October 21, 2003 |
2,5,-diazabicyclo[2.2.1]heptane derivatives, their preparation and
therapeutic uses
Abstract
The invention relates to 2,5-diazabicyclo[2.2.1]heptane
derivatives, to pharmaceutical compositions containing them, and to
methods for the treatment or prevention of disorders associated
with a dysfunction of the nicotinic receptors utilizing them.
Inventors: |
Lochead; Alistair (Charenton,
FR), Jegham; Samir (Montferrier sur Lez,
FR), Nedelec; Alain (Colombes, FR),
Jeunesse; Jean (Paris, FR), Galli; Frederic
(Vaucresson, FR), Even; Luc (Paris, FR) |
Assignee: |
Sanofi-Synthelabo (Paris,
FR)
|
Family
ID: |
9533581 |
Appl.
No.: |
09/856,946 |
Filed: |
August 16, 2001 |
PCT
Filed: |
December 01, 1999 |
PCT No.: |
PCT/FR99/02974 |
PCT
Pub. No.: |
WO00/34284 |
PCT
Pub. Date: |
June 15, 2000 |
Foreign Application Priority Data
|
|
|
|
|
Dec 4, 1998 [FR] |
|
|
98 15325 |
|
Current U.S.
Class: |
514/252.01;
514/252.04; 546/349; 546/330; 546/238; 514/269; 514/256;
514/252.11; 544/357; 544/359; 544/360 |
Current CPC
Class: |
A61P
43/00 (20180101); A61P 25/16 (20180101); A61P
25/04 (20180101); A61P 25/14 (20180101); A61P
25/18 (20180101); A61P 25/30 (20180101); A61P
25/22 (20180101); A61P 25/24 (20180101); A61P
25/28 (20180101); C07D 487/08 (20130101); A61P
9/10 (20180101); A61P 1/00 (20180101); A61P
25/00 (20180101) |
Current International
Class: |
C07D
487/08 (20060101); C07D 487/00 (20060101); C07D
487/08 (); A61K 031/44 (); A61K 031/501 (); A61K
031/506 (); A61P 025/28 () |
Field of
Search: |
;544/238,330,320,359,360,349,357
;514/256,269,252.14,247,252.01,252.11,252.04 |
References Cited
[Referenced By]
U.S. Patent Documents
|
|
|
4954502 |
September 1990 |
Smith et al. |
4994460 |
February 1991 |
Dextraze et al. |
5478939 |
December 1995 |
Trybulski et al. |
|
Other References
Clementi et al.European Journal of Pharmacology, 393, Mar. 10,
2000..
|
Primary Examiner: Shah; Mukund J.
Assistant Examiner: Balasubramanian; Venkataraman
Attorney, Agent or Firm: Alexander; Michael D.
Claims
What is claimed is:
1. A compound of formula (I) ##STR4##
in which one of the symbols X, Y and Z represents a nitrogen atom,
another represents a group of formula C--R.sub.3 and the third
represents a nitrogen atom or a group of formula C--R.sub.4,
R.sub.3 and R.sub.4 represent, independently of each other, a
hydrogen or halogen atom or a trifluoromethyl, cyano, hydroxyl,
(C.sub.1 -C.sub.6)alkyl or (C.sub.1 -C.sub.6)alkoxy group, R.sub.1
and R.sub.2 represent, independently of each other, a hydrogen or
halogen atom or a trifluoromethyl, cyano, hydroxyl, (C.sub.1
-C.sub.6)alkyl or (C.sub.1 -C.sub.6)alkoxy group, or a phenyl group
optionally substituted with one or two halogen atoms, with one or
two trifluoromethyl groups, with a cyano group, with a nitro group,
with a hydroxyl group, with a (C.sub.1 -C.sub.6)alkyl group, with
one or two (C.sub.1 -C.sub.6)alkoxy groups, with a methylenedioxy
group, with an acetyl group, with a trifluoromethoxy group or with
a methylthio group, R represents a hydrogen atom or a (C.sub.1
-C.sub.6)alkyl group, with the exclusion of the compounds of
formula (I) in which (a) Y and Z each represent a nitrogen atom,
(b) X and Z represent a nitrogen atom, Y represents a group CH, R
and R.sub.2 are hydrogen and R.sub.1 is fluorine, (c) X represents
a nitrogen atom, Z represents a group C(OCH.sub.3), Y represents a
group CH, and R, R.sub.1 and R.sub.2 are hydrogen, or (d) X
represents a nitrogen atom, Z represents a group CH, Y represents a
group CCl, and R, R.sub.1 and R.sub.2 are hydrogen
in base form or in the form of an addition salt with an acid.
2. A compound according to claim 1 wherein the heterocycle
containing X, Y and Z is a 3-pyridyl group.
3. A compound according to claim 1 wherein the heterocycle
containing X, Y and Z is a 3-pyridazinyl group.
4. A method for the treatment of disorders associated with a
dysfunction of the nicotinic receptors which comprises
administering to a patient in need of such treatment an effective
amount of a compound according to any one of claims 1 to 3.
5. A pharmaceutical composition which comprises a compound
according to any one of claims 1 to 3 together with an excipient.
Description
The compounds of the present invention correspond to the general
formula (I) ##STR1##
in which one of the symbols X, Y and Z represents a nitrogen atom,
another represents a group of formula C--R.sub.3 and the third
represents a nitrogen atom or a group of formula C--R.sub.4,
R.sub.3 and R.sub.4 represent, independently of each other, a
hydrogen or halogen atom or a trifluoromethyl, cyano, hydroxyl,
(C.sub.1 -C.sub.6)alkyl or (C.sub.1 -C.sub.6)alkoxy group, R.sub.1
and R.sub.2 represent, independently of each other, a hydrogen or
halogen atom or a trifluoromethyl, cyano, hydroxyl, (C.sub.1
-C.sub.6)alkyl or (C.sub.1 -C.sub.6)alkoxy group, or a phenyl group
optionally substituted with one or two halogen atoms, with one or
two trifluoromethyl groups, with a cyano group, with a nitro group,
with a hydroxyl group, with a (C.sub.1 -C.sub.6)alkyl group, with
one or two ##STR2## (C.sub.1 -C.sub.6)alkoxy groups, with a
methylenedioxy group, with an acetyl group, with a trifluoromethoxy
group or with a methylthio group, R represents a hydrogen atom or a
(C.sub.1 -C.sub.6)alkyl group, with the exclusion, however, of the
compounds of general formula (I) in which X represents a group of
formula CH, Y and Z each represent a nitrogen atom, and R.sub.1 or
R.sub.2 does not represent an optionally substituted phenyl
group.
The compounds thus excluded are described in U.S. Pat. No.
5,478,939 as muscarine agonists.
The compounds of the invention can exist in the form of bases or of
addition salts with acids. They can also exist in the form of (S,S)
or (R,R) isomers.
The preferred compounds are those in the formula of which the
heterocycle containing X, Y and Z is a 3-pyridyl or 3-pyridazinyl
group.
In accordance with the invention, and according to the preceding
scheme, the compounds of general formula (I) can be prepared by
reacting 1,1-dimethylethyl
2,5-diazabicyclo[2.2.1]heptane-2-carboxylate of formula (II) with a
heterocyclic compound of general formula (III), in which X, Y, Z,
R.sub.1 and R.sub.2 are as defined above and W represents a halogen
atom.
Thus, it is possible to carry out a Buchwald coupling (J. Org.
Chem. (1997) 62 6066-6068) in the presence of a palladium catalyst
such as palladium acetate,
tris(dibenzylideneacetone)dipalladium(0), etc., of a complexation
ligand such as triphenylphosphine, tributylphosphine or
2,2'-bis(diphenylphosphino)-1,1'-binaphthyl, and of a base, for
example an organic base such as sodium t-butoxide, or an inorganic
base such as caesium carbonate.
When X or Z represents a nitrogen atom, it is also possible to
carry out a standard nucleophilic substitution reaction in the
presence of a strong base such as caesium carbonate or
triethylamine.
A compound of general formula (IV) is obtained, in which, if so
desired, it is possible to modify the substituents R.sub.1 or
R.sub.2 ; for example, when R.sub.1 or R.sub.2 represents a halogen
atom, it can be substituted with an alkyl or phenyl group by a
Suzuki reaction, using an alkylboronic or phenylboronic acid, in
the presence of tetrakis(triphenylphosphine)palladium.
The compound of general formula (IV) is then deprotected in a known
manner, for example using trifluoroacetic acid or hydrochloric
acid, to give a compound of general formula (Ia), which corresponds
to the general formula (I) when R represents a hydrogen atom.
It is then possible, if so desired, to carry out an alkylation of
this compound, either by a reductive amination (formaldehyde and
sodium cyanoborohydride) or by an Eschweiler-Clarke reaction
(formaldehyde and formic acid).
1,1-Dimethylethyl (1S)-diazabicyclo[2.2.1]heptane-2-carboxylate of
formula (II) is described in J. Org. Chem. (1988) 53 1580-1582 and
1,1-dimethylethyl (1R)-diazabicyclo[2.2.1]heptane-2-carboxylate of
formula (II) is described in patent application EP-400,661.
The compounds of general formula (III) are commercially available
or are accessible by methods described in the literature.
The examples which follow illustrate the preparation of a number of
compounds of the invention. The elemental microanalyses and the IR
and NMR spectra confirm the structures of the compounds
obtained.
The numbers indicated in parentheses in the example titles
correspond to those in the first column of Table 1 given later.
In the compound names, the hyphen "-" forms part of the name, and
the underscore line "_" serves merely to indicate the line break;
it should be removed if a line break does not occur at that point,
and should not be replaced either with a normal hyphen or with a
space.
EXAMPLE 1
Compound 2
(1S)-2-(6-Chloro-3-pyridyl)-2,5-diazabicyclo[2.2.1]heptane
Hydrochloride (2:1)
1.1. 1,1-Dimethylethyl
(1S)-2-(6-chloro-3-pyridyl)-2,5-diazabicyclo[2.2.1]heptane-5-carboxylate
and 1,1-dimethylethyl
(1S)-2-(5-bromo-2-pyridyl)-2,5-diazabicyclo[2.2.1]heptane-5-carboxylate
4.96 g (25 mmol) of 1,1-dimethylethyl
(1S)-2,5-diazabicyclo[2.2.1]heptane-5-carboxylate, 5.0 g (26 mmol)
of 5-bromo-2-chloropyridine and 11.4 g (35 mmol) of caesium
carbonate suspended in 150 ml of tetrahydrofuran are placed into a
500 ml three-necked round-bottomed flask, a stream of nitrogen is
bubbled through for 15 min, 224 mg (1.0 mmol) of palladium(II)
acetate and 623 mg (1.0 mmol) of
2,2'-bis(diphenylphosphino)-1,1'-binaphthyl are added and the
mixture is refluxed for 22 h.
This mixture is filtered, the solvent is evaporated off and the
residue is purified by chromatography on a column of silica gel,
eluting with a 40/60 mixture of ethyl acetate and heptane. 1.63 g
of 1,1-dimethylethyl
(1S)-2-(5-bromo-2-pyridyl)-2,5-diazabicyclo[2.2.1]heptane-5-carboxylate,
melting point: 181-182.degree. C., [.alpha.].sub.D.sup.20
=-229.4.degree. (c=1, CH.sub.2 Cl.sub.2), and 3.65 g of
1,1-dimethylethyl
(1S)-2-(6-chloro-3-pyridyl)-2,5-diazabicyclo[2.2.1]heptane-5-carboxylate,
melting point: 189.degree. C., [.alpha.].sub.D.sup.20
=-224.5.degree. (c=1, CH.sub.2 Cl.sub.2), are obtained.
1.2. (1S)-2-(6-Chloro-3-pyridyl)-2,5-diazabicyclo[2.2.1]heptane
Hydrochloride (2:1)
3.0 g (9.71 mmol) of 1,1-dimethylethyl
(1S)-2-(6-chloro-3-pyridyl)-2,5-diazabicyclo[2.2.1]heptane-5-carboxylate
are dissolved in 250 ml of ethyl acetate in a 500 ml three-necked
round-bottomed flask and a stream of gaseous hydrogen chloride is
bubbled through for 30 min.
The solvent is evaporated off under reduced pressure, the residue
is taken up in 25 ml of ethyl acetate and the solid is collected by
filtration and recrystallized from 25 ml of ethanol.
2.39 g of dihydrochloride are obtained.
Melting point: 290-300.degree. C., [.alpha.].sub.D.sup.20
=-105.6.degree. (c=0.5, H.sub.2 O)
EXAMPLE 2
Compound 4
(1S)-2-(6-Chloro-3-pyridyl)-5-methyl-2,5-diazabicyclo[2.2.1]heptane
(E)-but-2-Enedioate (2:1)
0.55 g (2.65 mmol) of
(1S)-2-(6-chloro-3-pyridyl)-2,5-diazabicyclo[2.2.1]heptane
dissolved in 20 ml of ethanol is placed into a 100 ml three-necked
round-bottomed flask, the solution is cooled to 0.degree. C., 0.43
ml (5.31 mmol) of aqueous 37% formaldehyde solution is added
slowly, followed by portionwise addition of 0.334 g (5.31 mmol) of
sodium cyanoborohydride, while keeping the temperature close to
0.degree. C., and stirring is continued for 30 min.
The mixture is diluted with water and extracted with chloroform,
the organic phase is evaporated under reduced pressure and the
residue is purified by chromatography on a column of silica gel,
eluting with a 95/5/0.5 mixture of dichloromethane, methanol and
aqueous ammonia.
0.290 g of compound is obtained in the form of a base.
0.258 g of this product is dissolved in 20 ml of ethanol, the
solution is treated with 0.134 g of fumaric acid, the solvent is
evaporated off under reduced pressure and the solid is collected by
filtration.
0.292 g of fumarate is finally isolated.
Melting point: 143.6.degree. C., [.alpha.].sub.D.sup.20
=-94.5.degree. (c=0.5, H.sub.2 O)
EXAMPLE 3
Compound 6
(1S)-2-(6-Chloro-3-pyridazinyl)-2,5-diazabicyclo[2.2.1]heptane
Hydrochloride (2:1)
3.1. 1,1-Dimethylethyl
(1S)-2-(6-Chloro-3-pyridazinyl)-2,5-diazabicyclo[2.2.
1]heptane-5-carboxylate
0.397 g (2.0 mmol) of 1,1-dimethylethyl
(1S)-2,5-diazabicyclo[2.2.1]heptane-5-carboxylate, 0.328 g (2.2
mmol) of 3,6-dichloropyridazine and 1.3 g (4 mmol) of caesium
carbonate in 30 ml of toluene are placed into a 100 ml three-necked
round-bottomed flask and the mixture is refluxed for 48 h.
This mixture is filtered, the solvent is evaporated off under
reduced pressure and the residue is purified by chromatography on a
column of silica gel, eluting with an 80/20 mixture of ethyl
acetate and heptane.
0.3 g of compound is obtained.
Melting point: 198.degree. C.
3.2. (1S)-2-(6-Chloro-3-pyridazinyl)-2,5-diazabicyclo[2.2.1]heptane
Hydrochloride (2:1)
0.25 g (0.933 mmol) of 1,1-dimethylethyl
(1S)-2-(6-chloro-3-pyridazinyl)-2,5-diazabicyclo[2.2.
1]heptane-5-carboxylate and 20 ml of ethyl acetate are placed into
a 50 ml three-necked round-bottomed flask, gaseous hydrogen
chloride is bubbled through for 10 min and stirring is continued
for 30 min.
The solvent is evaporated off under reduced pressure, the residue
is taken up in 5 ml of ethyl acetate and the solid is collected by
filtration, rinsed with ethyl acetate and dried.
0.155 g of hydrochloride is obtained.
Melting point: 260-270.degree. C., [.alpha.].sub.D.sup.20
=-99.5.degree. (c=0.5, H.sub.2 O)
EXAMPLE 4
Compound 7
(1S)-2-(6-Phenyl-3-pyridazinyl)-2,5-diazabicyclo[2.2.1]heptane
4.1. 1,1-Dimethylethyl
(1S)-2-(6-Phenyl-3-pyridazinyl)-2,5-diazabicyclo[2.2.
1]heptane-5-carboxylate
1.0 g (5.0 mmol) of 1,1-dimethylethyl
(1S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate, 1.14 g (6.0
mmol) of 3-chloro-6-phenylpyridazine and 0.84 ml (6.0 mmol) of
triethylamine in 45 ml of toluene are introduced into a 100 ml
three-necked round-bottomed flask and the mixture is refluxed for
72 h.
The reaction medium is diluted with water, the organic phase is
separated out and the solvent is evaporated off under reduced
pressure. The residue is purified by chromatography on silica gel,
eluting with a 90/10 mixture of dichloromethane and acetone. 0.96 g
of product is thus obtained, which is triturated in diisopropyl
ether to isolate 0.92 g of pure product after drying.
Melting point: 208-209.degree. C.
4.2.
(1S)-2-(6-Phenyl-3-pyridazinyl)-2,5-diazabicyclo[2.2.1]heptane
0.9 g (2.55 mmol) of
(1S)-2-(6-phenyl-3-pyridazinyl)-2,5-diazabicyclo[2.2.
1]heptane-5-carboxylate and 25 ml of ethyl acetate are placed in a
100 ml three-necked round-bottomed flask, gaseous hydrogen chloride
is bubbled through for 10 min and stirring is continued for 30
min.
The solvent is evaporated off under reduced pressure and the
residue is taken up in aqueous potassium hydroxide solution and
extracted with chloroform. The chloroform phase is evaporated and
the residue obtained is triturated in diisopropyl ether to give
0.59 g of pure product.
Melting point: 162-163.degree. C., [.alpha.].sub.D.sup.20
=-187.8.degree. (c=0.5, CHCl.sub.3)
EXAMPLE 5
Compound 8
(1S)-2-(6-Phenyl-3-pyridazinyl)-5-methyl-2,5-diazabicyclo[2.2.1]heptane
0.439 g (1.74 mmol) of
(1S)-2-(6-phenyl-3-pyridazinyl)-2,5-diazabicyclo[2.2.1]heptane
dissolved in 15 ml of ethanol and 0.21 ml (3.48 mmol) of acetic
acid are placed in a 100 ml three-necked round-bottomed flask.
0.284 ml (3.48 mmol) of an aqueous formaldehyde solution is added,
followed by portionwise addition of 0.218 g (3.48 mmol) of sodium
cyanoborohydride, while keeping the temperature at about 5.degree.
C., and stirring is continued for 1 h.
The reaction medium is diluted with water, aqueous potassium
hydroxide solution is added and this mixture is extracted with
chloroform. The organic phase is evaporated under reduced pressure
and the residue obtained is purified by chromatography on a column
of silica gel, eluting with a 97/3/0.3 mixture of chloroform,
methanol and aqueous ammonia.
0.430 g of product is thus obtained, which is triturated in hot
diisopropyl ether to isolate, after drying, 0.392 g of
compound.
Melting point: 112.6-113.degree. C., [.alpha.].sub.D.sup.20
=-165.3.degree. (c=0.5, CHCl.sub.3)
EXAMPLE 6
Compound 9
(1S)-2-(5-Phenyl-3-pyridyl)-2,5-diazabicyclo[2.2.1]heptane
6.1. 1,1-Dimethylethyl
(1S)-2-(5-Bromo-3-pyridyl)-2,5-diazabicyclo[2.2.1]heptane-5-carboxylate
1.98 g (10 mmol) of 1,1-dimethylethyl
(1S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate, 7.1 g (30 mmol)
of 3,5-dibromopyridine and 4.56 g (14 mmol) of caesium carbonate
suspended in 100 ml of tetrahydrofuran are placed in a 250 ml
three-necked round-bottomed flask, a stream of nitrogen is bubbled
through for 15 min, 90 mg (0.4 mmol) of palladium diacetate and 249
mg (0.4 mmol) of 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl are
added and the reaction mixture is refluxed for 22 h.
The reaction medium is filtered and the filtrate is concentrated
under reduced pressure. The residue obtained is purified by
chromatography on silica gel, eluting with a 40/60 mixture of ethyl
acetate and heptane.
2.99 g of 1,1-dimethylethyl
(1S)-2-(5-bromo-3-pyridyl)-2,5-diazabicyclo[2.2.1]heptane-5-carboxylate
are thus obtained.
Melting point: 149.degree. C., [.alpha.].sub.D.sup.20
=-196.5.degree. (c=0.5, CH.sub.2 Cl.sub.2)
6.2. 1,1-Dimethylethyl
(1S)-2-(5-Phenyl-3-pyridyl)-2,5-diazabicyclo[2.2.1]heptane-5-carboxylate
8 ml of benzene, 147 mg (0.127 mmol) of
tetrakis(triphenylphosphine)palladium and 1.5 g (4.23 mmol) of
1,1-dimethylethyl
(1S)-2-(5-bromo-3-pyridyl)-2,5-diazabicyclo[2.2.1]heptane-5-carboxylate
are placed, under argon, in a 25 ml three-necked round-bottomed
flask, 4 ml of aqueous 2 M sodium carbonate solution, 0.568 g (4.66
mmol) of phenylboronic acid and 0.2 ml of ethanol are added and the
mixture is refluxed for 3 h.
The reaction medium is allowed to separate by settling and the
organic phase is chromatographed on silica gel, eluting with a
75/25 and then 90/10 mixture of ethyl acetate and heptane.
1.55 g of compound are obtained, which product is triturated in hot
diisopropyl ether to isolate 1.36 g of product.
Melting point: 163.5-164.degree. C., [.alpha.].sub.D.sup.20
=-194.9.degree. (c=0.5, CH.sub.2 Cl.sub.2)
6.3. (1S)-2-(5-Phenyl-3-pyridyl)-2,5-diazabicyclo[2.2.1]heptane
1.30 g (3.7 mmol) of 1,1-dimethylethyl
(1S)-2-(5-phenyl-3-pyridyl)-2,5-diazabicyclo[2.2.1]heptane-5-carboxylate
dissolved in 40 ml of ethyl acetate are placed in a 100 ml
three-necked round-bottomed flask, gaseous hydrogen chloride is
bubbled through for 30 min and the solvent is then evaporated
off.
The reaction medium is basified with aqueous ammonia and extracted
with chloroform. The solvent is evaporated off and the residue is
triturated in diethyl ether.
0.438 g of pure compound is thus obtained.
Melting point: 116-117.degree. C., [.alpha.].sub.D.sup.20 -134.9
(c=0.5, CH.sub.2 Cl.sub.2)
EXAMPLE 7
Compound 15
(1S)-2-(6-Phenyl-3-pyridyl)-2,5-diazabicyclo[2.2.1]heptane
7.1. 3-Bromo-6-phenylpyridine
10 g (42.2 mmol) of 2,5-dibromopyridine, 5.2 g (42.2 mmol) of
phenylboronic acid and 30 ml of benzene are placed in a 250 ml
three-necked round-bottomed flask, 1.5 g (1.3 mmol) of
tetrakis(triphenylphosphine)palladium, 30 ml of benzene and 30 ml
of aqueous 2 M sodium carbonate solution and 1.4 ml of ethanol are
added and the mixture is refluxed for 17 h.
The reaction medium is cooled and filtered, the organic phase is
separated out by settling, the solvent is evaporated off under
reduced pressure and the residue is purified by chromatography on
silica gel, eluting with a 70/30 mixture of heptane and
dichloromethane.
8.6 g of crude product are obtained, which product is
recrystallized from 7 ml of ethanol. 5.6 g of pure product are thus
obtained in the form of a white solid.
Melting point: 69-72.degree. C.
7.2. 1,1-Dimethylethyl
(1S)-2-(6-Phenyl-3-pyridyl)-2,5-diazabicyclo[2.2.1]heptane-5-carboxylate
40 ml of tetrahydrofuran, 1.59 g (8.0 mmol) of 1,1-dimethylethyl
(1S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate, 2.25 g (9.6
mmol) of 3-bromo-6-phenylpyridine, 3.65 g (11.2 mmol) of caesium
carbonate, 72 mg of palladium diacetate and 0.20 g (0.32 mmol) of
2,2'-bis(diphenylphosphino)-1,1'-binaphthyl are placed, under
nitrogen, in a 100 ml three-necked round-bottomed flask and the
mixture is refluxed for 18 h.
This mixture is filtered, the solvent is evaported off under
reduced pressure and the residue is purified by chromatography on
silica gel, eluting with a 40/60 mixture of ethyl acetate and
heptane, to give 2.9 g of crude product, which product is
triturated in diisopropyl ether.
2.4 g of pure product are thus obtained.
Melting point: 147.5.degree. C., [.alpha.].sub.D.sup.20 =-251.3
(c=0.5, CH.sub.2 Cl.sub.2)
7.3. (1S)-2-(6-Phenyl-3-pyridyl)-2,5-diazabicyclo[2.2.1]heptane
2.3 g (6.8 mmol) of 1,1-dimethylethyl
(1S)-2-(6-phenyl-3-pyridyl)-2,5-diazabicyclo[2.2.1]heptane-5-carboxylate
dissolved in 100 ml of ethyl acetate are placed in a 250 ml
three-necked round-bottomed flask and gaseous hydrogen chloride is
bubbled through for 30 min.
The solvent is evaporated off under reduced pressure and the
residue is triturated in ether. The residue is basified by addition
of aqueous sodium hydroxide solution and is extracted with
chloroform. The solvent is evaporated off under reduced pressure to
give 1.7 g of solid, which product is triturated in diisopropyl
ether. 1.52 g of product are thus obtained in the form of a white
solid.
Melting point: 121.5-122.degree. C., [.alpha.].sub.D.sup.20
=-178.7.degree. (c=0.5, CH.sub.2 Cl.sub.2)
The table which follows illustrates the chemical structures and
physical properties of a number of compounds of the invention. In
the "Salt" column, "-" denotes a compound in base form, "HBr"
denotes a hydrobromide, "HCl" denotes a hydrochloride, "fum"
denotes a fumarate, or (E)-but-2-enedioate, "ox" denotes an
oxalate, or ethanedioate, and ATFA@ denotes a trifluoroacetate.
TABLE (1) ##STR3## No. X Y Z R R.sub.1 R.sub.2 Salt m.p. (.degree.
C.) [.alpha.].sub.D.sup.20 (*) 1 CH N CH H H H HBr 2:1 268-270
-103.2.degree. 2 CH N CH H Cl H HCl 2:1 290-300 -105.6.degree. 3 CH
N CH CH.sub.3 H H -- oil -126.7.degree. 4 CH N CH CH.sub.3 Cl H
fum. 1:1 143.6 -94.5.degree. 5 N CH CH H Br H HCl 2:1 215-220
-99.5.degree. 6 N N CH H Cl H HCl 2:1 260-270 -99.5.degree. 7 N N
CH H C.sub.6 H.sub.5 H -- 162-163 -187.8 8 N N CH CH.sub.3 C.sub.6
H.sub.5 H -- 112.6-113 -165.3 9 CH N CH H H C.sub.6 H.sub.5 --
116-117 -134.9 10 N CH CH H C.sub.6 H.sub.5 H HCl 2:1 192-205
-108.1 11 N CH CH CH.sub.3 C.sub.6 H.sub.5 H -- 45-50 -170.4 12 CH
N CH H OCH.sub.3 H HCl 2:1 188-190 -85.7 13 CH N CH H Br H fum. 1:1
199-202 -81.8 14 CH N CH H H Br fum. 1:1 225-230 -76.5 15 CH N CH H
C.sub.6 H.sub.5 H -- 121.5-122 -178.7 16 CH N CH CH.sub.3 C.sub.6
H.sub.5 H -- 86.5-87 -174.1 17 CH N CH CH.sub.3 H C.sub.6 H.sub.5
ox. 2:1 191-192 -83.2 18 CH N CH H H 3,4-OCH.sub.2 O--C.sub.6
H.sub.3 TFA 2:1 150-151 -68.5 19 CH N CH H H 3,5-(CF.sub.3).sub.2
--C.sub.6 H.sub.3 TFA 2:1 176-177 -61.3 20 CH N CH H H
3-Cl--C.sub.6 H.sub.4 HBr 3:1 280 -70.5 21 CH N CH H H 2,4-Cl.sub.2
--C.sub.6 H.sub.3 TFA 2:1 128-129 -63.0 22 CH N CH H H 4-CH.sub.3
O--C.sub.6 H.sub.4 TFA 2:1 127-128 -69.0 23 CH N CH H H 4-CF.sub.3
--C.sub.6 H.sub.4 TFA 2:1 189-190 -65.0 24 CH N CH H H 4-CH.sub.3
--C.sub.6 H.sub.4 TFA 2:1 160-161 -71.5 25 CH N CH H H 3-Cl,
4-F-C.sub.6 H.sub.3 TFA 2:1 150 -67.7 26 CH N CH H H 4-F--C.sub.6
H.sub.4 HBr 2:1 >280 -76.2 27 CH N CH H H 3-CH.sub.3 CO--C.sub.6
H.sub.4 HBr 2:1 >280 -79.1 28 CH N CH H H 2-CH.sub.3 --C.sub.6
H.sub.4 TFA 2:1 157 -70.8 29 CH N CH H H 2-CH.sub.3 O--C.sub.6
H.sub.4 TFA 2:1 134 -64.7 30 CH N CH H H 2-Cl--C.sub.6 H.sub.4 TFA
2:1 139-140 -68.9 31 CH N CH H H 2,3-Cl.sub.2 --C.sub.6 H.sub.3 TFA
2:1 146-147 -66.5 32 CH N CH H H 3,4-Cl.sub.2 --C.sub.6 H.sub.3 TFA
2:1 140 -66.9 33 CH N CH H H 3-CF.sub.3 --C.sub.6 H.sub.4 TFA 2:1
126 -70.2 34 CH N CH H H 3-CH.sub.3 O--C.sub.6 H.sub.4 HBr 2:1 235
-76.3 35 CH N CH H H 3-CF.sub.3 O--C.sub.6 H.sub.4 TFA 2:1 165-166
-63.0 36 CH N CH H H 4-CH.sub.3 S--C.sub.6 H.sub.4 TFA 2:1 113
-66.7 37 CH N CH CH.sub.3 4-F--C.sub.6 H.sub.4 H 38 CH N CH
CH.sub.3 4-CH.sub.3 O--C.sub.6 H.sub.4 H 39 CH N CH CH.sub.3
2-CH.sub.3 O--C.sub.6 H.sub.4 H 40 CH N CH CH.sub.3 2-F--C.sub.6
H.sub.4 H 41 CH N CH CH.sub.3 3-CH.sub.3 --C.sub.6 H.sub.4 H 42 CH
N CH CH.sub.3 3-CH.sub.3 CO--C.sub.6 H.sub.4 H 43 CH N CH CH.sub.3
3-CF.sub.3 --C.sub.6 H.sub.4 H 44 CH N CH CH.sub.3 4-CF.sub.3
--C.sub.6 H.sub.4 H 45 CH N CH CH.sub.3 3,4-(CH.sub.3 O).sub.2
--C.sub.6 H.sub.3 H 46 CH N CH CH.sub.3 2,4-(CH.sub.3 O).sub.2
--C.sub.6 H.sub.3 H 47 CH N CH CH.sub.3 3-CH.sub.3 O--C.sub.6
H.sub.4 H 48 CH N CH CH.sub.3 3,4-OCH.sub.2 O--C.sub.6 H.sub.3 H 49
CH N CH CH.sub.3 4-CH.sub.3 --C.sub.6 H.sub.4 H 50 CH N CH CH.sub.3
3-F--C.sub.6 H.sub.4 H 51 CH N CH CH.sub.3 4-CH.sub.3 CH.sub.2
--C.sub.6 H.sub.4 H 52 CH N CH CH.sub.3 4-F, 3-Cl--C.sub.6 H.sub.3
H
The compounds of the invention underwent tests which demonstrated
their therapeutic properties.
Thus, they were studied as regards their affinity with respect to
nicotinic receptors containing the .alpha..sub.4.beta..sub.2
subunit according to the methods described by Anderson and Arneric,
Eur. J. Pharmacol (1994) 253 261, and by Hall et al., Brain Res.
(1993) 600 127.
Male Sprague Dawley rats weighing 150 to 200 g are decapitated and
the entire brain is removed quickly, homogenized in 15 volumes of
0.32 M sucrose solution at 4.degree. C. and then centrifuged at
1000.times.g for 10 min. The pellet is discarded and the
supernatant is centrifuged at 20,000.times.g for 20 min at
4.degree. C. The pellet is recovered and homogenized using a
Polytron.TM. mill in 15 volumes of double-distilled water at
4.degree. C., followed by centrifugation at 8000.times.g for 20
min. The pellet is discarded and the supernatant and the "buffy
coat" are centrifuged at 40,000.times.g for 20 min, the pellet is
recovered, resuspended in 15 ml of double-distilled water at
4.degree. C. and centrifuged again at 40,000.times.g, before being
stored at -80.degree. C.
On the day of the experiment, the tissue is thawed slowly and
suspended in 3 volumes of buffer. 150 .mu.l of this membrane
suspension are incubated at 4.degree. C. for 120 min in the
presence of 100 .mu.l of 1 nM [.sup.3 H]cytisine in a final volume
of 500 .mu.l of buffer, in the presence or absence of test
compound. The reaction is stopped by filtration on Whatman GF/B.TM.
filters pretreated with polyethyleneimine, the filters are rinsed
with 2.times.5 ml of buffer at 4.degree. C. and the radioactivity
retained on the filter is measured by liquid scintigraphy. The
non-specific binding is determined in the presence of 10 .mu.M
(-)-nicotine; the non-specific binding represents 75 to 85% of the
total binding recovered on the filter. For each concentration of
test compound, the percentage of inhibition of the specific binding
of [.sup.3 H]cytisine is determined, followed by calculating the
IC.sub.50 value, which is the concentration of compound which
inhibits the specific binding by 50%.
The IC.sub.50 values for the purest compounds of the invention is
between 0.001 and 0.25 .mu.M.
The compounds of the invention were also studied as regards their
affinity with respect to nicotinic receptors containing the
.alpha.7 subunit, according to the methods described by Marks and
Collins, J. Pharmacol. Exp. Ther. (1982) 22 554 and Marks et al.,
Mol. Pharmacol. (1986) 30 427.
Male OFA rats weighing 150 to 200 g are decapitated, the entire
brain is removed quickly and homogenized using a Polytron.TM. mill
in 15 volumes of a 0.32 M sucrose solution at 4.degree. C.,
followed by centrifugation at 1000.times.g for 10 min. The pellet
is discarded and the supernatant is centrifuged at 8000.times.g for
20 min at 4.degree. C. The pellet is recovered and homogenized
using a Polytron.TM. mill in 15 volumes of double-distilled water
at 4.degree. C., followed by centrifugation at 8000.times.g for 20
min. The pellet is discarded and the supernatant and the buffy coat
are centrifuged at 40,000.times.g for 20 min. The pellet is
recovered, resuspended with 15 volumes of double-distilled water at
4.degree. C. and centrifuged again at 40,000.times.g for 20 min,
before storing it at -80.degree. C.
On the day of the experiment, the tissue is thawed slowly and
suspended in 5 volumes of buffer. 150 .mu.l of this membrane
suspension is preincubated at 37.degree. C. for 30 min, in the
dark, in the presence or absence of the test compound. Next, the
membranes are incubated for 60 min at 37.degree. C., in the dark,
in the presence of 50 .mu.l of 1 nM [.sup.3 H].alpha.-bungarotoxin
in a final volume of 250 .mu.l of 20 mM HEPES, 0.05%
polyethyleneimine buffer. The reaction is stopped by filtration
through Whatman GF/C.TM. filters pretreated for 3 hours with 0.5%
polyethyleneimine. The filters are rinsed with 2.times.5 ml of
buffer at 4.degree. C. and the radioactivity retained on each
filter is measured by liquid scintigraphy. The non-specific binding
in the presence of .alpha.-bungarotoxin at 1 .mu.M final is
determined; the non-specific binding represents about 60% of the
total binding recovered on the filter. For each concentration of
test compound, the percentage of inhibition of the specific binding
of [.sup.3 H].alpha.-bungarotoxin is determined, followed by
calculating the IC.sub.50 value, which is the concentration of
compound which inhibits the specific binding by 50%.
The IC.sub.50 values for the purest compounds of the invention are
between 0.005 and 0.6 .mu.M.
The compounds of the invention were also studied as regards their
affinity with respect to peripheral nicotinic receptors of ganglion
type, according to the method described by Houghtling et al., Mol.
Pharmacol. (1995) 48 280-287. The capacity of a compound to
displace [.sup.3 H]-epibatidine from bovine adrenal gland membranes
measures its affinity for this receptor.
Bovine adrenal glands stored at -80.degree. C. are thawed and
homogenized using a Polytron.TM. mill, in 20 volumes of 50 mM
Tris-HCl buffer at pH 7.4 at 4.degree. C., followed by
centrifugation at 35,000.times.g for 10 min. The supernatant is
discarded and the pellet is resuspended in 30 volumes of 50 mM
Tris-HCl buffer at 4.degree. C. and re-homogenized, after which it
is recentrifuged at 35,000.times.g for 10 min. The final pellet is
taken up in 10 volumes of Tris-HCl buffer at 4.degree. C. 100 .mu.l
of membrane, i.e. 10 mg of fresh tissue, are incubated at
24.degree. C. for 3 h in the presence of 50 .mu.l of 0.66 nM final
[.sup.3 H]-epibatidine in a final volume of 250 .mu.l of buffer, in
the presence or absence of test compound. The reaction is stopped
by diluting the samples with 50 .mu.M Tris-HCl buffer at pH 7.4 at
4.degree. C., followed by filtration on Whatman GF/C.TM. filters
pretreated for 3 hours with 0.5% polyethyleneimine. The filters are
rinsed twice with 5 ml of buffer and the radioactivity retained on
the filter is measured by liquid scintigraphy. The non-specific
binding is determined in the presence of 2 mM final (-)-nicotine;
the non-specific binding represents 30 to 40% of the total binding
recovered on the filter. For each concentration of test compound,
the percentage of inhibition of the specific binding of [.sup.3
H]-epibatidine is determined, followed by calculating the IC.sub.50
value, which is the concentration of compound which inhibits the
specific binding by 50%.
The IC.sub.50 values for the compounds of the invention are between
0.1 and 20 .mu.M.
The results of the preceding tests show that certain compounds of
the invention are selective ligands for the
.alpha..sub.4.beta..sub.2, .alpha..sub.7 or .alpha..sub.3 subunits
of the nicotinic receptor and that others are mixed
.alpha..sub.4.beta..sub.2 and .alpha..sub.7,
.alpha..sub.4.beta..sub.2 and .alpha..sub.3, or .alpha..sub.7 and
.alpha..sub.3.
Finally, the compounds of the invention underwent tests which
demonstrated their analgesic properties. Thus, they were studied in
the hotplate model, according to the method by Eddy and Leimbach,
J. Pharmacol. Exp. Ther. (1953) 107 385-393 with the aim of
investigating and quantifying any analgesic effect. Mice weighing
20 to 30 g are subjected to a heat stimulus by contact of the paws
with a plate kept at a constant temperature of 57.5.degree. C. by a
thermostatically controlled water bath. The reaction time to the
pain, which is manifested by licking of the paws or jumping, is
measured. Thus, after the interval of pretreatment carried out
subcutaneously or orally (each batch consisting of eight animals
for the same pretreatment), the mice are placed individually on the
plate and the reaction time to the pain is measured. The animal is
removed from the plate immediately after manifestation of the pain.
The maximum exposure time to the stimulus is 30 seconds.
The mean reaction time and the standard error of mean (s.e.m.) are
expressed for each batch. A non-parametric variance analysis
(Kruskal-Wallis) is carried out on the entire batch. A Wilcoxon
test allows comparison of each treated batch with the control
batch. The differences are considered as statistically significant
at the 5% threshold.
This reaction time is significantly increased by the analgesics
mainly with central effects.
The compounds of the invention show activity in this test at doses
of between 0.3 and 30 mg/kg intraperitoneally or orally.
The results of the various tests suggest the use of the compounds
in the treatment or prevention of disorders associated with a
dysfunction of the nicotinic receptors, in particular on the
central nervous system or the gastrointestinal system.
On the central nervous system, these disorders comprise cognitive
impairment, more specifically memory impairment, but also attention
impairment, associated with Alzheimer's disease, pathological
ageing (Age Associated Memory Impairment, AAMI), Parkinson's
disease, trisomy 21 (Down's syndrome), Korsakoff's alcoholic
syndrome, vascular dementia (multi-infarct dementia, MID) and
attention deficit/hyperactivity disorder, ADHD).
The compounds of the invention may also be useful in the treatment
of the motor disorders observed in Parkinson's disease or other
neurological diseases such as Huntington's chorea, Tourette's
syndrome, tardive dyskinesia and hyperkinesia.
The compounds of the invention can also constitute a curative or
symptomatic treatment for cranial or medullary accidents and
traumas, cerebrovascular accidents and cerebral hypoxic episodes,
as well as other acute or chronic neurodegenerative diseases.
They can be used in psychiatric pathologies: schizophrenia,
depression, anxiety, panic attacks, compulsive and obsessive
behaviour.
They can prevent the symptoms due to withdrawal from tobacco, from
alcohol and from various substances which induce a dependence, such
as cocaine, LSD, cannabis and benzodiazepines.
Finally, they can be useful for the treatment of acute and
neuropathic pain.
On the gastrointestinal system, the compounds of the invention may
be useful in the treatment of Crohn's disease, ulcerous colitis,
irritable bowel syndrome and obesity.
To this end, the compounds of the invention can be in any
composition form which is suitable for enteral, parenteral or
transdermal administration, such as tablets, sugar-coated tablets,
gel capsules, wafer capsules, drinkable or injectable suspensions
or solutions such as syrups or ampules, transdermal patches, etc.,
combined with suitable excipients, and dosed to allow a daily
administration of from 0.01 to 20 mg/kg.
* * * * *